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Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye

Educational Objective
To understand the pathophysiology of exfoliation syndrome.
1 Credit CME
Key Points

Question  Is the presence of exfoliation syndrome, a common cause of glaucoma, associated with rare, protein-changing variants?

Findings  In this multicenter, case-control, whole-exome sequencing study that included 20 441 participants, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to be carriers of functionally deficient CYP39A1 alleles (odds ratio, 2.03).

Meaning  The presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants.

Abstract

Importance  Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective  To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, and Participants  A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures  Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes and Measures  The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10−6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results  The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10−7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions and Relevance  In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

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Article Information

Correction: This article was corrected on April 6, 2021, to update 2 incomplete author names in the following sections: Authors for the Genetics of Exfoliation Syndrome Partnership, Affiliations of Authors for the Genetics of Exfoliation Syndrome Partnership, and Author Contributions.

Accepted for Publication: January 14, 2021.

Corresponding Author: Chiea Chuen Khor, MD, PhD, Genome Institute of Singapore, 60 Biopolis St, 02-01 Genome Bldg, Singapore 138672 (khorcc@gis.a-star.edu.sg).

Authors for the Genetics of Exfoliation Syndrome Partnership: Zheng Li, MD, PhD; Zhenxun Wang, PhD; Mei Chin Lee, PhD; Matthias Zenkel, PhD; Esther Peh, BS; Mineo Ozaki, MD, PhD; Fotis Topouzis, MD, PhD; Satoko Nakano, MD; Anita Chan, MD; Shuwen Chen, BS; Susan E. I. Williams, MD, PhD; Andrew Orr, MD; Masakazu Nakano, PhD; Nino Kobakhidze, MD; Tomasz Zarnowski, MD, PhD; Alina Popa-Cherecheanu, MD, PhD; Takanori Mizoguchi, MD; Shin-ichi Manabe, MD, PhD; Ken Hayashi, MD, PhD; Shigeyasu Kazama, MD; Kenji Inoue, MD, PhD; Yosai Mori, MD, PhD; Kazunori Miyata, MD, PhD; Kazuhisa Sugiyama, MD, PhD; Tomomi Higashide, MD, PhD; Etsuo Chihara, MD, PhD; Ryuichi Ideta, MD, PhD; Satoshi Ishiko, MD, PhD; Akitoshi Yoshida, MD, PhD; Kana Tokumo, MD; Yoshiaki Kiuchi, MD, PhD; Tsutomu Ohashi, MD, PhD; Toshiya Sakurai, MD, PhD; Takako Sugimoto, MD; Hideki Chuman, MD, PhD; Makoto Aihara, MD, PhD; Masaru Inatani, MD, PhD; Kazuhiko Mori, MD, PhD; Yoko Ikeda, MD, PhD; Morio Ueno, MD, PhD; Daniel Gaston, PhD; Paul Rafuse, MD, PhD; Lesya Shuba, MD, PhD; Joseph Saunders, BS; Marcelo Nicolela, MD; George Chichua, MD; Sergo Tabagari, MD, PhD; Panayiota Founti, MD, PhD; Kar Seng Sim, MS; Wee Yang Meah, BS; Hui Meng Soo, BS; Xiao Yin Chen, BS; Anthi Chatzikyriakidou, PhD; Christina Keskini, MD; Theofanis Pappas, MD; Eleftherios Anastasopoulos, MD; Alexandros Lambropoulos, PhD; Evangelia S. Panagiotou, MD, PhD; Dimitrios G. Mikropoulos, MD, PhD; Ewa Kosior-Jarecka, MD; Augustine Cheong, BS; Yuanhan Li, MS; Urszula Lukasik, MD, PhD; Monisha E. Nongpiur, MD, PhD; Rahat Husain, MD; Shamira A. Perera, MD; Lydia Álvarez, PhD; Montserrat García, PhD; Héctor González-Iglesias, PhD; Andrés Fernández-Vega Cueto, MD, PhD; Luis Fernández-Vega Cueto, MD, PhD; Federico Martinón-Torres, MD, PhD; Antonio Salas, PhD; Çilingir Oguz, PhD; Nevbahar Tamcelik, MD; Eray Atalay, MD; Bilge Batu, MD; Murat Irkec, MD; Dilek Aktas, MD, PhD; Burcu Kasım, MD; Yury S. Astakhov, MD; Sergei Y. Astakhov, MD, PhD; Eugeny L. Akopov, MD, PhD; Andreas Giessl, PhD; Christian Mardin, MD; Claus Hellerbrand, MD; Jessica N. Cooke Bailey, PhD; Robert P. Igo Jr, PhD; Jonathan L. Haines, PhD; Deepak P. Edward, MD; Steffen Heegaard, MD; Sonia Davila, PhD; Patrick Tan, MD, PhD; Jae H. Kang, ScD; Louis R. Pasquale, MD; Friedrich E. Kruse, MD; André Reis, MD; Trevor R. Carmichael, MD; Michael Hauser, PhD; Michele Ramsay, PhD; Georg Mossböck, MD; Nilgun Yildirim, MD; Kei Tashiro, MD, PhD; Anastasios G. P. Konstas, MD, PhD; Miguel Coca-Prados, PhD; Jia Nee Foo, PhD; Shigeru Kinoshita, MD, PhD; Chie Sotozono, MD, PhD; Toshiaki Kubota, MD, PhD; Michael Dubina, MD, PhD; Robert Ritch, MD; Janey L. Wiggs, MD, PhD; Francesca Pasutto, PhD; Ursula Schlötzer-Schrehardt, PhD; Ying Swan Ho, PhD; Tin Aung, MD, PhD; Wai Leong Tam, PhD; Chiea Chuen Khor, MD, PhD.

Affiliations of Authors for the Genetics of Exfoliation Syndrome Partnership: Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore (Z. Li, Wang, Sim, Meah, Soo, X. Y. Chen, Cheong, Tan, Foo, Tam, Khor); Singapore Eye Research Institute, Singapore National Eye Centre, Singapore (Wang, Lee, Chan, Y. Li, Nongpiur, Husain, Perera, Aung, Khor); Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (Zenkel, Giessl, Mardin, Kruse, Schlötzer-Schrehardt); Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore (Peh, S. Chen, Ho); Ozaki Eye Hospital, Miyazaki, Japan (Ozaki); First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece (Topouzis, Founti, Keskini, Pappas, Anastasopoulos, Panagiotou, Mikropoulos); iScreen Research Team, Center for Interdisciplinary Research and Innovation, Aristotle University of Thessaloniki, Thessaloniki, Greece (Topouzis); Department of Ophthalmology, Faculty of Medicine, Oita University, Oita, Japan (S. Nakano, Kubota); Duke-NUS Medical School, Singapore (Chan, Nongpiur, Aung, Khor); Division of Ophthalmology, Department of Neurosciences, University of Witwatersrand, Johannesburg, South Africa (Williams, Carmichael); Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada (Orr, Rafuse, Shuba, Saunders, Nicolela); Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada (Orr, Gaston); Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan (M. Nakano, Tashiro); Chichua Medical Center Mzera, Tbilisi, Georgia (Kobakhidze, Chichua); Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland (Zarnowski, Kosior-Jarecka, Lukasik); Carol Davila University of Medicine and Pharmacy, Bucharest, Romania (Popa-Cherecheanu); Department of Ophthalmology, University Emergency Hospital, Bucharest, Romania (Popa-Cherecheanu); Mizoguchi Eye Hospital, Nagasaki, Japan (Mizoguchi); Hayashi Eye Hospital, Fukuoka, Japan (Manabe, Hayashi); Shinjo Eye Clinic, Miyazaki, Japan (Kazama); Inouye Eye Hospital, Tokyo, Japan (Inoue); Miyata Eye Hospital, Miyazaki, Japan (Y. Mori, Miyata); Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan (Sugiyama, Higashide); Sensho-kai Eye Institute, Kyoto, Japan (Chihara); Ideta Heisei Retina Consultants, Kumamoto, Japan (Ideta); Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan (Ishiko); Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan (Yoshida); Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan (Tokumo, Kiuchi); Ohashi Eye Center, Sapporo, Japan (Ohashi); Tane Memorial Eye Hospital, Osaka, Japan (Sakurai); Department of Ophthalmology, Miyazaki Medical College Hospital, Miyazaki, Japan (Sugimoto, Chuman); Department of Ophthalmology, University of Tokyo, Tokyo, Japan (Aihara); Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan (Inatani); Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan (K. Mori, Ikeda, Ueno, Sotozono); David Tvildiani Medical University, Tbilisi, Georgia (Tabagari); Glaucoma Unit, Moorfields Eye Hospital NHS Foundation Trust, London, England (Founti); Laboratory of Medical Biology–Genetics, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece (Chatzikyriakidou, Lambropoulos); Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain (Álvarez, García, González-Iglesias, A. Fernández-Vega Cueto, L. Fernández-Vega Cueto, Coca-Prados); Fernández-Vega Ophthalmological Institute, Oviedo, Spain (Álvarez, García, González-Iglesias, A. Fernández-Vega Cueto, L. Fernández-Vega Cueto, Coca-Prados); Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago and GENVIP Research Group, Instituto de Investigación Sanitaria, University of Santiago de Compostela, Santiago de Compostela, Spain (Martinón-Torres); Unidade de Xenética, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria, Hospital Clínico Universitario de Santiago, Galicia, Spain (Salas); Department of Genetics, Eskisehir Osmangazi University, Eskisehir, Turkey (Oguz); Faculty of Medicine, Istanbul University–Cerrahpasa, Istanbul, Turkey (Tamcelik, Batu); Department of Ophthalmology, Eskisehir Osmangazi University, Eskisehir, Turkey (Atalay, Yildirim); Department of Ophthalmology, Faculty of Medicine, Hacettepe University, Ankara, Turkey (Irkec, Kasım); DAMAGEN Genetic Diagnostic Center, Ankara, Turkey (Aktas); Department of Ophthalmology, Pavlov First Saint Petersburg State Medical University, St Petersburg, Russia (Y. S. Astakhov, S. Y. Astakhov, Akopov); Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany (Hellerbrand); Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio (Cooke Bailey, Igo Jr, Haines); King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia (Edward); Department of Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago (Edward); Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (Heegaard); Eye Pathology Section, Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (Heegaard); SingHealth Duke-NUS Institute of Precision Medicine, Singapore (Davila, Tan); Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore (Davila); Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore (Tan); Cancer Science Institute of Singapore, National University of Singapore, Singapore (Tan, Tam); Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Kang); Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York (Pasquale); Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany (Reis, Pasutto); Department of Medicine, Duke University, Durham, North Carolina (Hauser); Department of Ophthalmology, Duke University, Durham, North Carolina (Hauser); Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa (Ramsay); Department of Ophthalmology, Medical University Graz, Graz, Austria (Mossböck); First and Third Departments of Ophthalmology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece (Konstas); Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut (Coca-Prados); Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore (Foo); Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan (Kinoshita); State Research Institute of Highly Pure Biopreparations FMBA Russia, St Petersburg, Russia (Dubina); Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York (Ritch); Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston (Wiggs); Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Aung); Nanyang Technological University School of Biological Sciences, Singapore (Tam); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Tam).

Author Contributions: Dr Khor had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Z. Li, Wang, Lee, Zenkel, Pasutto, Schlötzer-Schrehardt, Ho, Aung, Tam, and Khor contributed to the work equally.

Concept and design: Z. Li, Wang, Lee, Zenkel, Mizoguchi, Kazama, Sugiyama, Aihara, A. Fernández-Vega Cueto, Irkec, Heegaard, Kruse, Tashiro, Kinoshita, Aung, Khor.

Acquisition, analysis, or interpretation of data: Z. Li, Wang, Lee, Zenkel, Peh, Ozaki, Topouzis, S. Nakano, Chan, S. Chen, Williams, Orr, M. Nakano, Kobakhidze, Zarnowski, Popa-Cherecheanu, Manabe, Hayashi, Inoue, Y. Mori, Miyata, Higashide, Chihara, Ideta, Ishiko, Yoshida, Tokumo, Kiuchi, Ohashi, Sakurai, Sugimoto, Chuman, Aihara, Inatani, K. Mori, Ikeda, Ueno, Gaston, Rafuse, Shuba, Saunders, Nicolela, Chichua, Tabagari, Founti, Sim, Meah, Soo, X. Chen, Chatzikyriakidou, Keskini, Pappas, Anastasopoulos, Lambropoulos, Panagiotou, Mikropoulos, Kosior-Jarecka, Cheong, Y. Li, Lukasik, Nongpiur, Husain, Perera, Álvarez, García, González-Iglesias, A. Fernández-Vega Cueto, L. Fernández-Vega Cueto, Martinón-Torres, Salas, Oguz, Tamcelik, Atalay, Batu, Aktas, Kasım, Y. Astakhov, S. Astakhov, Akopov, Giessl, Mardin, Hellerbrand, Cooke Bailey, Igo Jr, Haines, Edward, Heegaard, Davila, Tan, Kang, Pasquale, Reis, Carmichael, Hauser, Ramsay, Mossböck, Yildirim, Tashiro, Konstas, Coca-Prados, Foo, Sotozono, Kubota, Dubina, Ritch, Wiggs, Pasutto, Schlötzer-Schrehardt, Ho, Aung, Tam, Khor.

Drafting of the manuscript: Z. Li, Wang, Lee, Zenkel, Peh, S. Chen, Mizoguchi, Manabe, Kazama, Sugiyama, Ohashi, Sugimoto, Aihara, Inatani, Ikeda, Soo, X. Chen, Lambropoulos, Mikropoulos, Oguz, Tamcelik, Batu, Giessl, Cooke Bailey, Yildirim, Tashiro, Schlötzer-Schrehardt, Ho, Aung, Tam, Khor.

Critical revision of the manuscript for important intellectual content: Z. Li, Wang, Lee, Zenkel, Ozaki, Topouzis, S. Nakano, Chan, Williams, Orr, M. Nakano, Kobakhidze, Zarnowski, Popa-Cherecheanu, Hayashi, Inoue, Y. Mori, Miyata, Higashide, Chihara, Ideta, Ishiko, Yoshida, Tokumo, Kiuchi, Sakurai, Chuman, Aihara, K. Mori, Ueno, Gaston, Rafuse, Shuba, Saunders, Nicolela, Chichua, Tabagari, Founti, Sim, Meah, Chatzikyriakidou, Keskini, Pappas, Anastasopoulos, Panagiotou, Kosior-Jarecka, Cheong, Y. Li, Lukasik, Nongpiur, Husain, Perera, Álvarez, García, González-Iglesias, A. Fernández-Vega Cueto, L. Fernández-Vega Cueto, Martinón-Torres, Salas, Atalay, Irkec, Aktas, Kasım, Y. Astakhov, S. Astakhov, Akopov, Mardin, Hellerbrand, Igo Jr, Haines, Edward, Heegaard, Davila, Tan, Kang, Pasquale, Kruse, Reis, Carmichael, Hauser, Ramsay, Mossböck, Yildirim, Tashiro, Konstas, Coca-Prados, Foo, Kinoshita, Sotozono, Kubota, Dubina, Ritch, Wiggs, Pasutto, Ho, Aung, Tam, Khor.

Statistical analysis: Z. Li, Wang, Lee, Zenkel, Peh, Sim, A. Fernández-Vega Cueto, Cooke Bailey, Haines, Tashiro, Foo, Ho, Aung, Khor.

Obtained funding: Kazama, Sugimoto, Rafuse, Founti, Haines, Wiggs, Aung, Tam, Khor.

Administrative, technical, or material support: Z. Li, Wang, Lee, Peh, Ozaki, Topouzis, S. Nakano, S. Chen, M. Nakano, Zarnowski, Mizoguchi, Manabe, Inoue, Y. Mori, Sugiyama, Higashide, Chihara, Ideta, Ishiko, Yoshida, Tokumo, Kiuchi, Sakurai, Chuman, Inatani, K. Mori, Ueno, Tabagari, Founti, Meah, Soo, X. Chen, Chatzikyriakidou, Keskini, Pappas, Lambropoulos, Panagiotou, Mikropoulos, Kosior-Jarecka, Cheong, Y. Li, Nongpiur, Perera, Álvarez, García, González-Iglesias, A. Fernández-Vega Cueto, L. Fernández-Vega Cueto, Martinón-Torres, Salas, Tamcelik, Atalay, Batu, Irkec, Kasım, Astakhov, Akopov, Giessl, Mardin, Hellerbrand, Edward, Heegaard, Davila, Tan, Yildirim, Tashiro, Konstas, Kinoshita, Sotozono, Kubota, Dubina, Pasutto, Schlötzer-Schrehardt, Ho, Aung, Tam, Khor.

Supervision: Khor, Wang, Zenkel, Kobakhidze, Aihara, Chichua, Tabagari, Meah, Perera, Heegaard, Pasquale, Kruse, Reis, Carmichael, Ramsay, Coca-Prados, Ho, Aung, Tam, Khor.

Conflict of Interest Disclosures: Dr Topouzis reported receiving grants from Pfizer, Thea Pharmaceuticals, Novartis, Rheon, Alcon, Omikron, Bayer, and Bausch & Lomb; and receiving personal fees from Novartis and Omikron. Dr Chan reported receiving grants from Santen Pharmaceutical Co Ltd, Menarini Biomarker Singapore, and the National Medical Research Council. Dr Inoue reported receiving grants from Santen Pharmaceutical Co Ltd, Alcon Japan Ltd, Senju Pharmaceutical Co Ltd, Allergan Japan, and Teijin Pharma Limited; and receiving personal fees from Santen Pharmaceutical Co Ltd, Otsuka Pharmaceutical Co Ltd, Senju Pharmaceutical Co Ltd, Kowa Pharmaceutical Co Ltd, Allergan Japan, Novartis Pharma, Wakamoto Pharmaceutical Co Ltd, Hoya Corporation, Carl Zeiss Meditec, and Pfizer Japan Inc. Dr Y. Mori reported receiving grants from Alcon, AMO Pharma Ltd, Hoya Corporation, Otsuka Pharmaceutical, and Mitsubishi Chemical Medience; and receiving personal fees from Alcon, Hoya Corporation, Santen Pharmaceutical Co Ltd, AMO Pharma Ltd, and Novartis. Dr Ideta reported receiving personal fees from Santen Pharmaceutical Co Ltd, Senjyu, and Kowa. Dr K. Mori reported receiving grants from the Japan Society for the Promotion of Science; receiving personal fees from Santen Pharmaceutical Co Ltd, Kowa, and Senju Pharmaceutical Co; and having a patent pending with Santen Pharmaceutical Co Ltd that is unrelated to the article. Dr Nicolela reported receiving grants from Allergan Inc, Aerie Pharmaceutics, and Alcon Canada; and receiving personal fees from Allergan Canada, Baush & Lomb Canada, and Labtician-Thea. Dr Founti reported receiving personal fees from Thea Pharmaceuticals. Dr Pasquale reported receiving personal fees from Bausch & Lomb, Nicox, Verily, Eyenovia, and Emerald Biosciences. Dr Konstas reported receiving grants from Allergan, Santen Pharmaceutical Co Ltd, Pharmaten, and Omni Vision; and receiving personal fees from Merck Sharp and Dohme, Vianex, and Santen Pharmaceutical Co Ltd. Dr Kinoshita reported receiving grants from Santen Pharmaceutical Co Ltd, Senju Pharmaceutical Co, Otsuka Pharmaceutical, Kowa, Hoya Corporation, Oncolys Biopharma Inc, Lion Corporation, and CorneaGen; and receiving personal fees from Santen Pharmaceutical Co Ltd, Alcon Japan, AMO Pharma Ltd, Novartis, Astellas Pharma, Senju Pharmaceutical Co, Otsuka Pharmaceutical, Kowa, CorneaGen, and Aerie Pharmaceuticals. No other disclosures were reported.

Funding/Support: The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Yin Ying Ho, PhD (Bioprocessing Technology Institute); and Matias Autio, PhD, and Tan Lek Wen, PhD (both with the Genome Institute of Singapore), for technical support without receiving compensation.

Additional Information: Coauthor Yury S. Astakhov, MD, died on June 10, 2020, and coauthor Robert P. Igo Jr, PhD, died on July 19, 2020.

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